Combination therapy may help combat treatment resistance in cancer patients.
Through a bioinformatics analysis, investigators identified 10 previously untested drug combinations that may provide a future treatment option for breast cancer.
In a study published in Cancer Research, investigators conducted an in silico analysis of 64 paired therapeutic agents used to treat breast cancer. Half of the drugs were already in use, while the other half are in clinical trials.
Of the 10 combinations tested in breast tumor cells in vitro, 7 had a high level of synergy. Furthermore, 1 combination was validated in mice, according to the study.
“We identify many more synergistic combinations in silico than combinatorial assays do until now with high-performance lab techniques, and we can provide experimental details,” said study author Patrick Aloy. “This implies that prior computational analyses give better results and are more reliable.”
In mouse models, the combination of raloxifene and cabozantinib dramatically increased the anti-tumor effects of each cancer drug. Furthermore, joint effects of the 2 drugs were much greater in 70% of the tested combinations compared with the effects of each drug alone. This means the same effect could be achieved with a smaller dose, according to the study.
The findings showed that the raloxifene and cabozantinib combination treatment in mice caused the tumors to shrink by 60%, while the effect of the drugs alone only prevented further tumor growth.
Compared with current treatments, the combination regimen—–with a dose that is 3 and 25 times smaller, respectively––can be used.
“That in itself is very important because drugs are in fact toxic and are used to kill cells,” Aloy said. “If, by using a smaller dose, a greater—–or even the same––chemotherapeutic effect is achieved, it is a significant advantage with respect to reducing the side effects experienced by patients. Also, in principle, resistance would be avoided for delayed.”
A prominent issue in oncology is the onset of treatment resistance. In 15% of cases, alternative molecular signaling pathways are activated to allow tumor cells to divide again or evade apoptosis, according to the study. Combination therapy, however, may be a promising approach for combating treatment resistance.
“Our analyses have allowed us to predict the signaling pathways that are inactivated by the joint action of 2 drugs,” said first study author Samira Jaeger.
At a molecular level, the investigators validated the inhibition of the molecules predicted in the in silico model.
“By combining drugs, we aim to attack the tumor cell simultaneously from various flanks, thus making it more difficult for the cell to resist treatment, as the pathways that allow it to survive and proliferate will be knocked out the same time,” Jaeger said.
The investigative team is now working on 3 different research lines, according to the study. With the goal to move towards clinical applications, the investigators will test combined treatment with raloxifene and cabozantinib in tumors obtained from patients and transplanted in mice.
The lab will also focus on pairing an anti-tumor agent with a drug administered for other conditions, such as diabetes and high blood pressure, to help find more effective breast cancer treatments.
Additionally, the investigators are tweaking an experimental method that would allow them to validate the combined therapies that show the greatest long-term efficacy in addressing treatment resistance.